Mogat1 is a fasting‐induced PPARα target gene that plays a role in coordinating the hepatic response to food deprivation

Abstract

During prolonged fasting, the liver plays a central role in maintaining systemic energy homeostasis by producing glucose and ketones in processes fueled by oxidation of fatty acids liberated from adipose tissue. In mice, this is also accompanied by transient hepatic accumulation of complex lipids in the form of triglycerides. In mice fasted for 24 hours, the hepatic expression of Mogat1 was significantly increased compared to mice given ad libitum access to food. Mogat1 encodes an enzyme with monoacylglycerol (MAG) acyltransferase (MGAT) activity, which is an understudied step in glycerolipid synthesis. Basal and fasting‐induced expression of Mogat1 was markedly diminished in liver of mice lacking the transcription factor peroxisome proliferator‐activated receptor α (PPARα). Suppressing Mogat1 expression with antisense‐oligonucleotides (ASO) reduced hepatic MGAT activity and hepatic triglyceride content compared to fasted ASO control treated mice. Surprisingly, the expression of many other known PPARα target genes (Dgat1, Mgll, Cpt1α, Acadm, and Acadl) was also decreased in mice treated with Mogat1 ASO. We postulated that inhibiting Mogat1 suppressed PPARα activity, potentially by loss of a ligand for PPARα. Fasted mice treated with control or Mogat1 ASO were gavaged with the synthetic PPARα ligand WY‐14643, which reversed the effects of Mogat1 ASO on liver triglyceride content as well as PPARα target gene expression. In conclusion, Mogat1 is a fasting‐induced PPARα target gene and MGAT and may feed forward to regulate liver PPARα activity during fasting.Support or Funding InformationA.J.L. was supported by funds from NIH training grant T32 DK07120. K.S.M is supported by K99 HL136658 and A.M.H. is supported by 17‐IBS‐109 from the American Diabetes Association and R56 DK111735. This work was also funded by R01 DK078187 to B.N.F. The Core services of the Diabetes Research Center (P30 DK020579) and the Nutrition Obesity Research Center (P30 DK56341) at the Washington University School of Medicine also supported this work.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.